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Abstract Background Identifying clusters of multiple long-term conditions (MLTCs), also known as multimorbidity, and their associated burden may facilitate the development of effective and cost-effective targeted healthcare strategies. This study aimed to identify clusters of MLTCs and their associations with long-term health-related quality of life (HRQoL) in two UK population-based cohorts. Methods Age-stratified clusters of MLTCs were identified at baseline in UK Biobank (n = 502,363, 54.6% female) and UKHLS (n = 49,186, 54.8% female) using latent class analysis (LCA). LCA was applied to people who self-reported ≥ 2 LTCs (from n = 43 LTCs [UK Biobank], n = 13 LTCs [UKHLS]) at baseline, across four age-strata: 18–36, 37–54, 55–73, and 74 + years. Associations between MLTC clusters and HRQoL were investigated using tobit regression and compared to associations between MLTC counts and HRQoL. For HRQoL, we extracted EQ-5D index data from UK Biobank. In UKHLS, SF-12 data were extracted and mapped to EQ-5D index scores using a standard preference-based algorithm. HRQoL data were collected at median 5 (UKHLS) and 10 (UK Biobank) years follow-up. Analyses were adjusted for available sociodemographic and lifestyle covariates. Results LCA identified 9 MLTC clusters in UK Biobank and 15 MLTC clusters in UKHLS. Clusters centred around pulmonary and cardiometabolic LTCs were common across all age groups. Hypertension was prominent across clusters in all ages, while depression featured in younger groups and painful conditions/arthritis were common in clusters from middle-age onwards. MLTC clusters showed different associations with HRQoL. In UK Biobank, clusters with high prevalence of painful conditions were consistently associated with the largest deficits in HRQoL. In UKHLS, clusters of cardiometabolic disease had the lowest HRQoL. Notably, negative associations between MLTC clusters containing painful conditions and HRQoL remained significant even after adjusting for number of LTCs. Conclusions While higher LTC counts remain important, we have shown that MLTC cluster types also have an impact on HRQoL. Health service delivery planning and future intervention design and risk assessment of people with MLTCs should consider both LTC counts and MLTC clusters to better meet the needs of specific populations.

Abstract Background Multiple long-term conditions (MLTCs), living with two or more long-term conditions (LTCs), often termed multimorbidity, has a high and increasing prevalence globally with earlier age of onset in people living in deprived communities. A holistic understanding of the patient’s perspective of the work associated with living with MLTCs is needed. This study aimed to synthesise qualitative evidence describing the experiences of people living with MLTCs (multimorbidity) and to develop a greater understanding of the effect on people’s lives and ways in which living with MLTCs is 'burdensome' for people. Methods Three concepts (multimorbidity, burden and lived experience) were used to develop search terms. A broad qualitative filter was applied. MEDLINE (Ovid), EMBASE (Ovid), PsycINFO (EBSCO), CINAHL (EBSCO) and the Cochrane Library were searched from January 2000-January 2023. We included studies where at least 50% of study participants were living with three or more LTCs and the lived experience of MLTCs was expressed from the patient perspective. Screening and quality assessment (CASP checklist) was undertaken by two independent researchers. Data was synthesised using an inductive approach. PPI (Patient and Public Involvement) input was included throughout. Results Of 30,803 references identified, 46 met the inclusion criteria. 31 studies (67%) did not mention ethnicity or race of participants and socioeconomic factors were inconsistently described. Only two studies involved low- and middle-income countries (LMICs). Eight themes of work were generated: learning and adapting; accumulation and complexity; symptoms; emotions; investigation and monitoring; health service and administration; medication; and finance. The quality of studies was generally high. 41 papers had no PPI involvement reported and none had PPI contributor co-authors. Conclusions The impact of living with MLTCs was experienced as a multifaceted and complex workload involving multiple types of work, many of which are reciprocally linked. Much of this work, and the associated impact on people, may not be apparent to healthcare staff, and current health systems and policies are poorly equipped to meet the needs of this growing population. There was a paucity of data from LMICs and insufficient information on how patient characteristics might influence experiences. Future research should involve patients as partners and focus on these evidence gaps.

Abstract There is uncertainty about how best to diagnose asthma, especially in primary care where mis-diagnosis is common. To address this, we developed a clinical decision support system (CDSS) for asthma diagnosis in children and young people (aged 5-25 years). This study explored the feasibility and acceptability of the CDSS in UK primary care. We recruited general practices from England and Scotland. The CDSS was available for use during routine consultations for six months. We analysed CDSS usage and, toward the end of the study, undertook qualitative interviews with clinicians who had used the CDSS. Within the 10 practices who completed the study, the CDSS was used by 75 out of 94 clinicians. 11 clinicians from 8 practices were interviewed. The CDSS was acceptable to participants who particularly commented on the ease of use and auto-population of information from the patient record. Barriers to use included the inability to record findings directly into the patient notes and a sense that, whilst possibly useful for trainees and junior colleagues, the CDSS would not necessarily lead to a change in their own practice. The CDSS was generally well received by primary care clinicians, though participants felt it would be most useful for trainees and less experienced colleagues.

Abstract Background The common Eastern bumble bee Bombus impatiens is native to North America and is the main commercially reared pollinator in the Americas. There has been extensive research on this species related to its social biology, applied pollination, and genetics. The genome of this species was previously sequenced using short-read technology, but recent technological advances provide an opportunity for substantial improvements. This species is common in agricultural and urban environments, and heavy metal contaminants produced by industrial processes can negatively impact it. To begin to identify possible mechanisms underlying responses to these toxins, we used RNA-sequencing to examine how exposure to a cocktail of four heavy metals at field-realistic levels from industrial areas affected B. impatiens worker gene expression. Results PacBio long-read sequencing resulted in 544x coverage of the genome, and HiC technology was used to map chromatin contacts. Using Juicer and manual curation, the genome was scaffolded into 18 main pseudomolecules, representing a high quality, chromosome-level assembly. The sequenced genome size is 266.6 Mb and BRAKER3 annotation produced 13,938 annotated genes. The genome and annotation show high completeness, with ≥ 96% of conserved Eukaryota and Hymenoptera genes present in both the assembly and annotated genes. RNA sequencing of heavy metal exposed workers revealed 603 brain and 34 fat body differentially expressed genes. In the brain, differentially expressed genes had biological functions related to chaperone activity and protein folding. Conclusions Our data represent a large improvement in genomic resources for this important model species—with 10% more genome coverage than previously available, and a high-quality assembly into 18 chromosomes, the expected karyotype for this species. The new gene annotation added 777 new genes. Altered gene expression in response to heavy metal exposure suggests a possible mechanism for how these urban toxins are negatively impacting bee health, specifically by altering protein folding in the brain. Overall, these data are useful as a general high quality genomic resource for this species, and provide insight into mechanisms underlying tissue-specific toxicological responses of bumble bees to heavy metals.

Background People with low back pain (LBP) are often recommended to self-manage their condition, but it can be challenging without support. Digital health interventions (DHIs) have shown promise in supporting self-management of LBP, but little is known about healthcare providers’ (HCPs) engagement in implementing these. Aims We aimed to examine HCPs’ engagement in patient recruitment for the selfBACK app clinical trial and explore their perceptions of the app. Methods In a mixed-methods design, we conducted a process evaluation alongside the selfBACK trial, triangulating quantitative data from trial recruitment logs and a vignette-based survey, and qualitative data from trial procedure documents, interviews with HCPs, and survey free-text responses. From 2019 to 2020, we recruited 57 HCPs from Norway and 39 health clinics in Denmark and collected quantitative and qualitative data in parallel. Results were integrated using displays. Results Overall, 825 patients were recruited by the HCPs. The vignette-based survey showed high agreement among HCPs (n = 62) with the self-management plans generated by the app (84.1–88.9%) but also highlighted concerns about tailoring and content. Interviews with HCPs (n = 19) revealed challenges with recruitment due to busy schedules, competing tasks, and varying levels of interest and engagement in the study. Conclusions The study identified factors that impact HCPs’ engagement in recruiting patients for the selfBACK trial and highlighted overall positive views of the selfBACK app, although some concerns about the content and tailoring of the app were raised. Understanding HCP motivations and workload is crucial for the successful implementation of DHIs in clinical practice.

The role of biomarkers in risk-based early detection of lung cancer may enable screening to become cost effective and widely accessible. EarlyCDT-Lung is an example of such a blood-based autoantibody biomarker which may improve accessibility to Low dose Computed Tomography (LDCT) screening for those at highest risk. We randomized 12 208 individuals aged 50-75 at high risk of developing lung cancer to either the test or to standard clinical care. Outcomes were ascertained from Register of Deaths and Cancer Registry. Cox proportional hazards models were used to estimate the hazard ratio of the rate of deaths from all causes and lung cancer. Additional analyses were performed for cases of lung cancer diagnosed within two years of the initial test. After 5 years 326 lung cancers were detected (2.7% of those enrolled). The total number of deaths reported from all causes in the intervention group was 344 compared to 388 in the control group. There were 73 lung cancer deaths in the intervention arm and 90 in the controls (Adjusted HR 0.789 (0.636, 0.978). An analysis of cases of lung cancer detected within 2 years of randomization in the intervention group showed that there were 34 deaths from all causes and 29 from lung cancer. In the control group there were 56 deaths with 49 from lung cancer. In those diagnosed with lung cancer within 2 years of randomization the hazard ratio for all cause mortality was 0.615 (0.401,0.942) and for lung cancer 0.598 (0.378, 0.946). Further large-scale studies of the role of biomarkers to target lung cancer screening, in addition to LDCT, are likely to provide additional value.

Abstract Background Current clustering of multimorbidity based on the frequency of common disease combinations is inadequate. We estimated the causal relationships among prevalent diseases and mapped out the clusters of multimorbidity progression among them. Methods In this cohort study, we examined the progression of multimorbidity among 190 diseases among over 500,000 UK Biobank participants over 12.7 years of follow-up. Using a machine learning method for causal inference, we analyzed patterns of how diseases influenced and were influenced by others in females and males. We used clustering analysis and visualization algorithms to identify multimorbidity progress constellations. Results We show the top influential and influenced diseases largely overlap between sexes in chronic diseases, with sex-specific ones tending to be acute diseases. Patterns of diseases that influence and are influenced by other diseases also emerged (clustering significance P au > 0.87), with the top influential diseases affecting many clusters and the top influenced diseases concentrating on a few, suggesting that complex mechanisms are at play for the diseases that increase the development of other diseases while share underlying causes exist among the diseases whose development are increased by others. Bi-directional multimorbidity progress presents substantial clustering tendencies both within and across International Classification Disease chapters, compared to uni-directional ones, which can inform future studies for developing cross-specialty strategies for multimorbidity. Finally, we identify 10 multimorbidity progress constellations for females and 9 for males (clustering stability, adjusted Rand index >0.75), showing interesting differences between sexes. Conclusion Our findings could inform the future development of targeted interventions and provide an essential foundation for future studies seeking to improve the prevention and management of multimorbidity.

Background The COVID-19 pandemic affected healthcare delivery globally, impacting care access and delivery of essential services. Objectives We investigated the pandemic’s impact on care for patients with type 2 diabetes and factors associated with care disruption in Kenya and Tanzania. Methods A cross-sectional study was conducted among adults diagnosed with diabetes pre-COVID-19. Data were collected in February–April 2022 reflecting experiences at two time-points, three months before and the three months most affected by the COVID-19 pandemic. A questionnaire captured data on blood glucose testing, changes in medication prescription and access, and healthcare provider access. Results We recruited 1000 participants (500/country). Diabetes care was disrupted in both countries, with 34.8% and 32.8% of the participants reporting change in place and frequency of testing in Kenya, respectively. In Tanzania, 12.4% and 17.8% reported changes in location and frequency of glucose testing, respectively. The number of health facility visits declined, 14.4% (p

ABSTRACT Introduction There is a paucity of research on and a limited understanding of patient and public involvement (PPI) in the context of research in homelessness and, in particular, direct involvement of people with lived and living experience of homelessness (PEH) as expert advisors. We aim to report on outcomes and reflections from lived experience advisory panel (LEAP) meetings and PPI activities, held throughout the study lifecycle of a pilot randomised‐controlled trial (RCT) focused on evaluating integrated health and practical support for PEH. Methods Community Pharmacy Homeless Outreach Engagement Non‐medical Independent prescribing Rx (PHOENIx Community Pharmacy RCT) is an integrated health and social care intervention for people experiencing homelessness who present to community pharmacy. Intervention includes weekly support from a pharmacist prescriber and a third sector support worker for up to 6 months. PPI activities undertaken throughout the study were documented, including outcomes of LEAP meetings. Outcome reporting followed Guidance for Reporting Involvement of Patients and the Public 2 Short Form (GRIPP2‐SF). Results In total, 17 members were recruited into the LEAP; six meetings (three in two study sites) were held. PPI input was also received through representation from homelessness third sector organisation staff as study co‐applicants and core membership in the trial steering committee. Together, the PPI activities helped shape the study proposal, design of study materials, data analysis and dissemination materials. LEAP panel members offered valuable input via their experience and expertise into the delivery and refinement of interventions. Although longitudinal input was received from some LEAP members, ensuring repeat attendance in the pre‐planned meetings was challenging. Conclusion People who face social exclusion and marginalisation can provide highly valuable input as equal partners in co‐design and delivery of interventions seeking to improve their health and well‐being. Fluid membership and flexible methods of seeking and incorporating advice can offer pragmatic approaches to minimising barriers to continued involvement in research. Patient or Public Contribution This study reports findings and learning relevant to involvement of people with lived and living experience of homelessness as advisors in a research study. It is important for researchers to offer fluid memberships and use diverse methods to receive input from lived experience members, as traditional PPI methodology may be insufficient to ensure inclusivity. Staff and volunteers from third sector organisations were important PPI partners who bring their experience based on frontline service provision, often as the first port of call for people experiencing severe and multiple disadvantage. Trial Registration ISRCTN88146807.

ABSTRACT Introduction Unhealthy lifestyle factors, such as smoking, high alcohol intake, poor diet and physical inactivity, are key risk factors for premature mortality. How unhealthy lifestyle factors are viewed in the wider context of socioeconomic deprivation is rarely considered. Understanding key stakeholder views on lifestyle factors in the context of deprivation is critical to intervention development and reducing harm in more deprived populations. The aim of this study was to explore public, healthcare professional and policymaker views around unhealthy lifestyle factors in the context of deprivation. The aim was broad to facilitate iterative development of ideas, as the views of this wide range of stakeholders are rarely captured. Methods Twenty‐five adult members of the public in Scotland took part in four focus groups between August 2022 and June 2023. Eighteen semi‐structured interviews were conducted with professionals: 12 primary‐care practitioners and 6 public‐health practitioners and policymakers. Reflexive thematic analysis was undertaken. Results Four main themes were developed: (1) Evolving complexity of lifestyle factors – the number of lifestyle factors that adversely impact health has grown, with increasingly complex interactions, (2) Social determinants of lifestyle – numerous links were made between socioeconomic conditions and unhealthy lifestyle factors by all participants, (3) Poverty as a fundamental social determinant – poverty was identified as a core factor for unhealthy lifestyle factors, and (4) Agency versus structure in relation to lifestyle – individual agency to address lifestyle factors was limited by structural constraints. Among professionals, understanding the challenging social determinants of unhealthy lifestyle factors was countered by a desire to support healthy change in those affected by deprivation. Conclusion Public and professional views around lifestyle highlight an evolving understanding of the new and growing number of lifestyle factors as well as the increasingly complex interplay between lifestyle factors. Views of the social determinants of lifestyle and structural limits to agency strengthen arguments for reduced emphasis on individual‐level responsibility for unhealthy lifestyle factors and for deeper integration of social determinants into lifestyle interventions. In addition to addressing poverty and socioeconomic inequalities directly, innovative policy, planning and legislation that incorporate wider approaches could tackle upstream determinants of numerous unhealthy lifestyle factors simultaneously. Patient or Public Contribution Members of the public who participated in this study have made contributions by sharing their views and perspectives. The National Health Service Research Scotland Primary Care Patient and Public Involvement (NRS PPI) Group contributed to the development of this work. The NRS PPI Group was consulted as part of the preparatory work for H. M. E. F.'s doctoral thesis funding application. The findings of the qualitative work were presented to them, and they informed the interpretation of those findings and related work presented at conferences and public engagement events.

Background: Diagnostic blood tests have the potential to identify lung cancer in people at high risk. We assessed the cost-effectiveness of a lung cancer screening intervention, using the EarlyCDT®-Lung Test (ECLS) with subsequent X-ray and low-dose chest CT scans (LDCT) for patients with a positive test result, compared to both usual care and LDCT screening for the target population. Methods: We conducted a model-based lifetime analysis from a UK NHS and personal social services perspective. We estimated incremental net monetary benefit (NMB) for the ECLS intervention compared to no screening and to LDCT screening. Results: The incremental NMB of ECLS intervention compared to no screening was GBP 33,179 (95% CI: −GBP 81,396, GBP 147,180) and GBP 140,609 (95% CI: −GBP 36,255, GBP 316,612), respectively, for a cost-effectiveness threshold of GBP 20,000 and GBP 30,000 per quality-adjusted life year. The same figures compared with LDCT screening were GBP 162,095 (95% CI: GBP 52,698, GBP 271,735) and GBP 52,185 (95% CI: −GBP 115,152, GBP 219,711). Conclusions: The ECLS intervention is the most cost-effective screening alternative, with the highest probability of being cost-effective, when compared to no screening or LDCT screening. This result may change with modifications of the parameters, suggesting that the three alternatives considered in the main analysis are potentially cost-effective.

Abstract Cardiac fibrosis contributes to the development of heart failure, and is the response of cardiac fibroblasts (CFs) to pressure or volume overload. Limiting factors in CFs research are the poor availability of human cells and the tendency of CFs to transdifferentiate into myofibroblasts when cultured in vitro. The possibility to generate CFs from induced pluripotent stem cells (iPSC), providing a nearly unlimited cell source, opens new possibilities. However, the behaviour of iPSC-CFs under mechanical stimulation has not been studied yet. Our study aimed to assess the behaviour of iPSC-CFs under mechanical stretch and pro-fibrotic conditions. First, we confirm that iPSC-CFs are comparable to primary CFs at gene, protein and functional level. Furthermore, iPSC-derived CFs adopt a pro-fibrotic response to transforming growth factor beta (TGF-β). In addition, mechanical stretch inhibits TGF-β-induced fibroblast activation in iPSC-CFs. Thus, the responsiveness to cytokines and mechanical stimulation of iPSC-CFs demonstrates they possess key characteristics of primary CFs and may be useful for disease modelling.

Abstract Different rat strains are used in various animal models of pulmonary hypertension and right ventricular (RV) failure. No systematic assessment has been made to test differences in RV response to pressure overload between rat strains. We compared RV adaptation to pulmonary trunk banding (PTB) in Wistar (W), Sprague Dawley (SD), and Fischer344 (F) rats by hemodynamic profiling focusing on diastolic function. Age‐matched male rat weanlings were randomized to sham surgery (W‐sham, n = 5; SD‐sham, n = 4; F‐sham, n = 4) or PTB (W‐PTB, n = 8; SD‐PTB, n = 8; F‐PTB, n = 8). RV function was evaluated after 5 weeks by echocardiography, cardiac MRI, and invasive pressure‐volume measurements. PTB caused RV failure and increased RV systolic pressures four‐fold in all three PTB groups compared with sham. W‐ and SD‐PTB had a 2.4‐fold increase in RV end‐systolic volume index compared with sham, while F‐PTB rats were less affected. Diastolic and right atrial impairment were evident by increased RV end‐diastolic elastance, filling pressure, and E/e' in PTB rats compared with sham, again F‐PTB the least affected. In conclusions, PTB caused RV failure with signs of diastolic dysfunction. Despite a similar increase in RV systolic pressure, F‐PTB rats showed less RV dilatation and a more preserved diastolic function compared with W‐ and SD‐PTB.

Objectives To examine randomised controlled trial (RCT) progression criteria including emergency department (ED) attendance and non-fatal overdose, from a holistic, integrated health and social care outreach intervention (PHOENIx), for people experiencing homelessness with recent non-fatal street drug overdose.Design Pilot RCT. 1:1 randomisation to PHOENIx plus usual care (UC) or UC.Setting Glasgow, Scotland.Participants 128 adults experiencing homelessness with at least one non-fatal street drug overdose in the preceding 6 months.Interventions Pharmacists from the National Health Service and third sector homelessness workers offered weekly outreach. PHOENIx teams develop therapeutic relationships to address health (physical health, mental health and problem drug use) and social care (housing, welfare benefits and social prescribing) in addition to UC. UC comprised building-based primary and secondary health, social and third sector services.Outcomes Primary: progression criteria: recruitment (≥100 participants in 4 months); ≥80% of participants with data collected at baseline, 6 and 9 months; ≥60% of participants retained in the trial at each follow-up period (6 and 9 months); ≥60% of participants receiving the intervention weekly; any reduction in the rate of presentation to ED and overdoses, at 6- or 9-month follow-up. Secondary: participants with, and time to: hospitalisations; health-related quality of life (QoL); treatment uptake for physical and mental health conditions, and problematic drug use.Results Progression criteria were exceeded. In PHOENIx compared with UC, there appeared to be a delay in the median time to ED visit, overdose and hospitalisation but no improvement in number of participants with ED visits, overdoses or hospitalisations. QoL and treatment uptake appeared to be higher in PHOENIx versus UC at 6 and 9 months.Conclusions A definitive RCT is merited, to assess the impact of PHOENIx on people with multiple, severe disadvantages.Trial registration number ISRCTN10585019.

Abstract Frailty, social isolation, and loneliness have individually been associated with adverse health outcomes. This study examines how frailty in combination with loneliness or social isolation is associated with socioeconomic deprivation and with all-cause mortality and hospitalisation rate in a middle-aged and older population. Baseline data from 461,047 UK Biobank participants (aged 37–73) were used to assess frailty (frailty phenotype), social isolation, and loneliness. Weibull models assessed the association between frailty in combination with loneliness or social isolation and all-cause mortality adjusted for age/sex/smoking/alcohol/socioeconomic-status and number of long-term conditions. Negative binomial regression models assessed hospitalisation rate. Frailty prevalence was 3.38%, loneliness 4.75% and social isolation 9.04%. Frailty was present across all ages and increased with age. Loneliness and social isolation were more common in younger participants compared to older. Co-occurrence of frailty and loneliness or social isolation was most common in participants with high socioeconomic deprivation. Frailty was associated with increased mortality and hospitalisation regardless of social isolation/loneliness. Hazard ratios for mortality were 2.47 (2.27–2.69) with social isolation and 2.17 (2.05–2.29) without social isolation, 2.14 (1.92–2.38) with loneliness and 2.16 (2.05–2.27) without loneliness. Loneliness and social isolation were associated with mortality and hospitalisation in robust participants, but this was attenuated in the context of frailty. Frailty and loneliness/social isolation affect individuals across a wide age spectrum and disproportionately co-occur in areas of high deprivation. All were associated with adverse outcomes, but the association between loneliness and social isolation and adverse outcomes was attenuated in the context of frailty. Future interventions should target people living with frailty or loneliness/social isolation, regardless of age.

Abstract Background Exposure to per- and poly-fluoroalkyl substances (PFAS) has been associated with significant alterations in female reproductive health. These include changes in menstrual cyclicity, timing of menarche and menopause, and fertility outcomes, as well as increased risk of endometriosis, all of which may contribute to an increased risk of endometrial cancer. The effect of PFAS on endometrial cancer cells, specifically altered treatment response and biology, however, remains poorly studied. Like other gynecologic malignancies, a key contributor to lethality in endometrial cancer is resistance to chemotherapeutics, specifically to platinum-based agents that are used as the standard of care for patients with advanced-stage and/or recurrent disease. Objectives To explore the effect of environmental exposures, specifically PFAS, on platinum-based chemotherapy response and mitochondrial function in endometrial cancer. Methods HEC-1 and Ishikawa endometrial cancer cells were exposed to sub-cytotoxic nanomolar and micromolar concentrations of PFAS/PFAS mixtures and were treated with platinum-based chemotherapy. Survival fraction was measured 48-h post-chemotherapy treatment. Mitochondrial membrane potential was evaluated in both cell lines following exposure to PFAS ± chemotherapy treatment. Results HEC-1 and Ishikawa cells displayed differing outcomes after PFAS exposure and chemotherapy treatment. Cells exposed to PFAS appeared to be less sensitive to carboplatin, with instances of increased survival fraction, indicative of platinum resistance, observed in HEC-1 cells. In Ishikawa cells treated with cisplatin, PFAS mixture exposure significantly decreased survival fraction. In both cell lines, increases in mitochondrial membrane potential were observed post-PFAS exposure ± chemotherapy treatment. Discussion Exposure of endometrial cancer cell lines to PFAS/PFAS mixtures had varying effects on response to platinum-based chemotherapies. Increased survival fraction post-PFAS + carboplatin treatment suggests platinum resistance, while decreased survival fraction post-PFAS mixture + cisplatin exposure suggests enhanced therapeutic efficacy. Regardless of chemotherapy sensitivity status, mitochondrial membrane potential findings suggest that PFAS exposure may affect endometrial cancer cell mitochondrial functioning and should be explored further.

Abstract Background Components of social connection are associated with mortality, but research examining their independent and combined effects in the same dataset is lacking. This study aimed to examine the independent and combined associations between functional and structural components of social connection and mortality. Methods Analysis of 458,146 participants with full data from the UK Biobank cohort linked to mortality registers. Social connection was assessed using two functional (frequency of ability to confide in someone close and often feeling lonely) and three structural (frequency of friends/family visits, weekly group activities, and living alone) component measures. Cox proportional hazard models were used to examine the associations with all-cause and cardiovascular disease (CVD) mortality. Results Over a median of 12.6 years (IQR 11.9–13.3) follow-up, 33,135 (7.2%) participants died, including 5112 (1.1%) CVD deaths. All social connection measures were independently associated with both outcomes. Friends/family visit frequencies

Abstract Aims Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and left ventricular diastolic dysfunction has been related to impaired energy homeostasis. This study investigated whether trimetazidine, a fatty acid oxidation inhibitor, could improve myocardial energy homeostasis and consequently improve exercise haemodynamics in patients with HFpEF. Methods and results The DoPING‐HFpEF trial was a phase II single‐centre, double‐blind, placebo‐controlled, randomized cross‐over trial. Patients were randomized to trimetazidine treatment or placebo for 3 months and switched after a 2‐week wash‐out period. The primary endpoint was change in pulmonary capillary wedge pressure, measured with right heart catheterization at multiple stages of bicycling exercise. Secondary endpoint was change in myocardial phosphocreatine/adenosine triphosphate, an index of the myocardial energy status, measured with phosphorus‐31 magnetic resonance spectroscopy. The study included 25 patients (10/15 males/females; mean (standard deviation) age, 66 (10) years; body mass index, 29.8 (4.5) kg/m2); with the diagnosis of HFpEF confirmed with (exercise) right heart catheterization either before or during the trial. There was no effect of trimetazidine on the primary outcome pulmonary capillary wedge pressure at multiple levels of exercise (mean change 0 [95% confidence interval, 95% CI −2, 2] mmHg over multiple levels of exercise, P = 0.60). Myocardial phosphocreatine/adenosine triphosphate in the trimetazidine arm was similar to placebo (1.08 [0.76, 1.76] vs. 1.30 [0.95, 1.86], P = 0.08). There was no change by trimetazidine compared with placebo in the exploratory parameters: 6‐min walking distance (mean change of −6 [95% CI −18, 7] m vs. −5 [95% CI −22, 22] m, respectively, P = 0.93), N‐terminal pro‐B‐type natriuretic peptide (5 (−156, 166) ng/L vs. −13 (−172, 147) ng/L, P = 0.70), overall quality‐of‐life (KCCQ and EQ‐5D‐5L, P = 0.78 and P = 0.51, respectively), parameters for diastolic function measured with echocardiography and cardiac magnetic resonance, or metabolic parameters. Conclusions Trimetazidine did not improve myocardial energy homeostasis and did not improve exercise haemodynamics in patients with HFpEF.

Abstract This article examines technical use of Fitbit during an intervention for pulmonary hypertension (PAH)‐patients. Technical issues with the device led to data being unavailable(37.5%). During intervention objective daily physical activity (DPA) decreased and subjective DPA increased. This emphasizes that an assessment of DPA in PAH requires incorporating both objective and subjective measurements.

Abstract Background Primary care and other health services have been disrupted during the COVID-19 pandemic, yet the consequences of these service disruptions on patients’ care experiences remain largely unstudied. People with mental-physical multimorbidity are vulnerable to the effects of the pandemic, and to sudden service disruptions. It is thus essential to better understand how their care experiences have been impacted by the current pandemic. This study aims to improve understanding of the care experiences of people with mental-physical multimorbidity during the pandemic and identify strategies to enhance these experiences. Methods We will conduct a mixed-methods study with multi-phase approach involving four distinct phases. Phase 1 will be a qualitative descriptive study in which we interview individuals with mental-physical multimorbidity and health professionals in order to explore the impacts of the pandemic on care experiences, as well as their perspectives on how care can be improved. The results of this phase will inform the design of study phases 2 and 3. Phase 2 will involve journey mapping exercises with a sub-group of participants with mental-physical multimorbidity to visually map out their care interactions and experiences over time and the critical moments that shaped their experiences. Phase 3 will involve an online, cross-sectional survey of care experiences administered to a larger group of people with mental disorders and/or chronic physical conditions. In phase 4, deliberative dialogues will be held with key partners to discuss and plan strategies for improving the delivery of care to people with mental-physical multimorbidity. Pre-dialogue workshops will enable us to synthesize an prepare the results from the previous three study phases. Discussion Our study results will generate much needed evidence of the positive and negative impacts of the COVID-19 pandemic on the care experiences of people with mental-physical multimorbidity and shed light on strategies that could improve care quality and experiences.

The importance of informal caregiving for chronic illness has been well established in African contexts but is underexplored in the context of HIV/NCD multimorbidity, particularly in South Africa. Building on treatment burden theories that investigate workload in the context of chronic illness, this paper explores how informal caregiving networks impact the capacity of people living with multimorbidity (PLWMM) in low-income settings in urban and rural South Africa. Qualitative semi-structured interviews were carried out with thirty people living with multimorbidity and sixteen informal caregivers between February and April 2021 in two settings, Cape Town (urban) and Bulungula (rural). Interviews were transcribed and data analysed both inductively and deductively using framework analysis, hereby, building on the principles of the burden of treatment theory (BoTT) as a theoretical lens. Our findings show that informal carers provided different types of support to people living with multimorbidity, including emotional, logistical, health services and informational support to ease the patient's treatment burden. Additional support networks, access to grants or financial security, and feeling a duty to care eased the perceived carer burden while a lack of social support, financial hardship and insufficient information decreased their capacity to support others. Overall, the availability of informal caregiving increases the self-management capacity of people living with multimorbidity in low-income settings in South Africa. Informal caregiving in the context of multimorbidity is structured through social obligations, kinship connections, cultural expectations, and an individual sense of agency. Carers, even when committed to assist, also experience caregiving opportunity costs, which are rarely addressed in the literature. By proposing interventions that can actively support informal caregivers, we can begin to develop solutions that can optimize the role of informal care networks, with a view to improve health-outcomes of PLWMM in South Africa.

Introduction: One major obstacle in validating drugs for the treatment or prevention of hearing loss is the limited data available on the distribution and concentration of drugs in the human inner ear. Although small animal models offer some insights into inner ear pharmacokinetics, their smaller organ size and different barrier (round window membrane) permeabilities compared to humans can complicate study interpretation. Therefore, developing a reliable large animal model for inner ear drug delivery is crucial. The inner and middle ear anatomy of domestic pigs closely resembles that of humans, making them promising candidates for studying inner ear pharmacokinetics. However, unlike humans, the anatomical orientation and tortuosity of the porcine external ear canal frustrates local drug delivery to the inner ear.Methods: In this study, we developed a surgical technique to access the tympanic membrane of pigs. To assess hearing pre- and post-surgery, auditory brainstem responses to click and pure tones were measured. Additionally, we performed 3D segmentation of the porcine inner ear images and used this data to simulate the diffusion of dexamethasone within the inner ear through fluid simulation software (FluidSim).Results: We have successfully delivered dexamethasone and dexamethasone sodium phosphate to the porcine inner ear via the intratympanic injection. The recorded auditory brainstem measurements revealed no adverse effects on hearing thresholds attributable to the surgery. We have also simulated the diffusion rates for dexamethasone and dexamethasone sodium phosphate into the porcine inner ear and confirmed the accuracy of the simulations using in-vivo data.Discussion: We have developed and characterized a method for conducting pharmacokinetic studies of the inner ear using pigs. This animal model closely mirrors the size of the human cochlea and the thickness of its barriers. The diffusion time and drug concentrations we reported align closely with the limited data available from human studies. Therefore, we have demonstrated the potential of using pigs as a large animal model for studying inner ear pharmacokinetics.

IntroductionAntipsychotic medication is increasingly prescribed to patients with serious mental illness. Patients with serious mental illness often have cardiovascular and metabolic comorbidities, and antipsychotics independently increase the risk of cardiometabolic disease. Despite this, many patients prescribed antipsychotics are discharged to primary care without planned psychiatric review. We explore perceptions of healthcare professionals and managers/directors of policy regarding reasons for increasing prevalence and management of antipsychotics in primary care.MethodsQualitative study using semi-structured interviews with 11 general practitioners (GPs), 8 psychiatrists, and 11 managers/directors of policy in the United Kingdom. Data was analysed using thematic analysis.ResultsRespondents reported competency gaps that impaired ability to manage patients prescribed antipsychotic medications, arising from inadequate postgraduate training and professional development. GPs lacked confidence to manage antipsychotic medications alone; psychiatrists lacked skills to address cardiometabolic risks and did not perceive this as their role. Communication barriers, lack of integrated care records, limited psychology provision, lowered expectation towards patients with serious mental illness by professionals, and pressure to discharge from hospital resulted in patients in primary care becoming 'trapped' on antipsychotics, inhibiting opportunities to deprescribe. Organisational and contractual barriers between services exacerbate this risk, with socioeconomic deprivation and lack of access to non-pharmacological interventions driving overprescribing. Professionals voiced fears of censure if a catastrophic event occurred after stopping an antipsychotic. Facilitators to overcome these barriers were suggested.ConclusionsPeople prescribed antipsychotics experience a fragmented health system and suboptimal care. Several interventions could be taken to improve care for this population, but inadequate availability of non-pharmacological interventions and socioeconomic factors increasing mental distress need policy change to improve outcomes. The role of professionals' fear of medicolegal or regulatory censure inhibiting antipsychotic deprescribing was a new finding in this study.

IntroductionStructured medication reviews (SMRs), introduced in the United Kingdom (UK) in 2020, aim to enhance shared decision-making in medication optimisation, particularly for patients with multimorbidity and polypharmacy. Despite its potential, there is limited empirical evidence on the implementation of SMRs, and the challenges faced in the process. This study is part of a larger DynAIRx (Artificial Intelligence for dynamic prescribing optimisation and care integration in multimorbidity) project which aims to introduce Artificial Intelligence (AI) to SMRs and develop machine learning models and visualisation tools for patients with multimorbidity. Here, we explore how SMRs are currently undertaken and what barriers are experienced by those involved in them.MethodsQualitative focus groups and semi-structured interviews took place between 2022-2023. Six focus groups were conducted with doctors, pharmacists and clinical pharmacologists (n = 21), and three patient focus groups with patients with multimorbidity (n = 13). Five semi-structured interviews were held with 2 pharmacists, 1 trainee doctor, 1 policy-maker and 1 psychiatrist. Transcripts were analysed using thematic analysis.ResultsTwo key themes limiting the effectiveness of SMRs in clinical practice were identified: 'Medication Reviews in Practice' and 'Medication-related Challenges'. Participants noted limitations to the efficient and effectiveness of SMRs in practice including the scarcity of digital tools for identifying and prioritising patients for SMRs; organisational and patient-related challenges in inviting patients for SMRs and ensuring they attend; the time-intensive nature of SMRs, the need for multiple appointments and shared decision-making; the impact of the healthcare context on SMR delivery; poor communication and data sharing issues between primary and secondary care; difficulties in managing mental health medications and specific challenges associated with anticholinergic medication.ConclusionSMRs are complex, time consuming and medication optimisation may require multiple follow-up appointments to enable a comprehensive review. There is a need for a prescribing support system to identify, prioritise and reduce the time needed to understand the patient journey when dealing with large volumes of disparate clinical information in electronic health records. However, monitoring the effects of medication optimisation changes with a feedback loop can be challenging to establish and maintain using current electronic health record systems.

Abstract Background Frailty and dementia have a bidirectional relationship. However, frailty is rarely reported in clinical trials for dementia and mild cognitive impairment (MCI) which limits assessment of trial applicability. This study aimed to use a frailty index (FI)—a cumulative deficit model of frailty—to measure frailty using individual participant data (IPD) from clinical trials for MCI and dementia. Moreover, the study aimed to quantify the prevalence of frailty and its association with serious adverse events (SAEs) and trial attrition. Methods We analysed IPD from dementia (n = 1) and MCI (n = 2) trials. An FI comprising physical deficits was created for each trial using baseline IPD. Poisson and logistic regression were used to examine associations with SAEs and attrition, respectively. Estimates were pooled in random effects meta-analysis. Analyses were repeated using an FI incorporating cognitive as well as physical deficits, and results compared. Results Frailty could be estimated in all trial participants. The mean physical FI was 0.14 (SD 0.06) and 0.14 (SD 0.06) in the MCI trials and 0.24 (SD 0.08) in the dementia trial. Frailty prevalence (FI > 0.24) was 6.9%/7.6% in MCI trials and 48.6% in the dementia trial. After including cognitive deficits, the prevalence was similar in MCI (6.1% and 6.7%) but higher in dementia (75.4%). The 99th percentile of FI (0.31 and 0.30 in MCI, 0.44 in dementia) was lower than in most general population studies. Frailty was associated with SAEs: physical FI IRR = 1.60 [1.40, 1.82]; physical/cognitive FI IRR = 1.64 [1.42, 1.88]. In a meta-analysis of all three trials, the estimated association between frailty and trial attrition included the null (physical FI OR = 1.17 [0.92, 1.48]; physical/cognitive FI OR = 1.16 [0.92, 1.46]), although higher frailty index values were associated with attrition in the dementia trial. Conclusion Measuring frailty from baseline IPD in dementia and MCI trials is feasible. Those living with more severe frailty may be under-represented. Frailty is associated with SAEs. Including only physical deficits may underestimate frailty in dementia. Frailty can and should be measured in future and existing trials for dementia and MCI, and efforts should be made to facilitate inclusion of people living with frailty.

Abstract Background Drug-related deaths in Scotland are the highest in Europe. Half of all deaths in people experiencing homelessness are drug related, yet we know little about the unmet health needs of people experiencing homelessness with recent non-fatal overdose, limiting a tailored practice and policy response to a public health crisis. Methods People experiencing homelessness with at least one non-fatal street drug overdose in the previous 6 months were recruited from 20 venues in Glasgow, Scotland, and randomised into PHOENIx plus usual care, or usual care. PHOENIx is a collaborative assertive outreach intervention by independent prescriber NHS Pharmacists and third sector homelessness workers, offering repeated integrated, holistic physical, mental and addictions health and social care support including prescribing. We describe comprehensive baseline characteristics of randomised participants. Results One hundred and twenty-eight participants had a mean age of 42 years (SD 8.4); 71% male, homelessness for a median of 24 years (IQR 12–30). One hundred and eighteen (92%) lived in large, congregate city centre temporary accommodation. A quarter (25%) were not registered with a General Practitioner. Participants had overdosed a mean of 3.2 (SD 3.2) times in the preceding 6 months, using a median of 3 (IQR 2–4) non-prescription drugs concurrently: 112 (87.5%) street valium (benzodiazepine-type new psychoactive substances); 77 (60%) heroin; and 76 (59%) cocaine. Half (50%) were injecting, 50% into their groins. 90% were receiving care from Alcohol and Drug Recovery Services (ADRS), and in addition to using street drugs, 90% received opioid substitution therapy (OST), 10% diazepam for street valium use and one participant received heroin-assisted treatment. Participants had a mean of 2.2 (SD 1.3) mental health problems and 5.4 (SD 2.5) physical health problems; 50% received treatment for physical or mental health problems. Ninety-one per cent had at least one mental health problem; 66% had no specialist mental health support. Participants were frail (70%) or pre-frail (28%), with maximal levels of psychological distress, 44% received one or no daily meal, and 58% had previously attempted suicide. Conclusions People at high risk of drug-related death continue to overdose repeatedly despite receiving OST. High levels of frailty, multimorbidity, unsuitable accommodation and unmet mental and physical health care needs require a reorientation of services informed by evidence of effectiveness and cost-effectiveness. Trial registration UK Clinical Trials Registry identifier: ISRCTN 10585019.

Abstract Background Recurrent focal segmental glomerulosclerosis (FSGS) after kidney transplantation (KT) is a serious complication and a significant risk factor for graft failure. However, there is no clear evidence of the effectiveness of pre-transplant treatment using plasmapheresis (PP) or rituximab in preventing post-operative FSGS recurrence after KT. Methods This single-center retrospective study included 99 adult patients with biopsy-proven primary FSGS who underwent KT between 2007 and 2018. The patients were divided into the pre-treatment group (N = 53, 53.5%) and no pre-treatment group (N = 46, 46.5%). In the pre-transplant group, prophylactic PP was administered before KT in patients undergoing living donor transplantation and the day after KT in those undergoing deceased donor transplantation. Results The rate of immediate post-operative recurrence was significantly higher in the no pre-treatment group (16 [34.8%]) than in the pre-treatment group (5 [9.4%]; P = 0.002). There were three cases of graft failure due to recurrent FSGS, all of which were in the no pre-treatment group. After adjusting for possible confounding factors, age (per 10-year increase; OR = 0.61, CI, 0.42–0.90; P = 0.012) and pre-transplant treatment (vs. no pre-transplant treatment; OR = 0.17, CI, 0.05–0.54; P = 0.003) were identified as significant factors associated with FSGS recurrence. The rate of death-censored graft survival was significantly superior in the pretransplant treatment group (P = 0.042). Conclusion Pre-transplant treatment with PP was associated with beneficial effects on preventing FSGS recurrence after KT.

Abstract Background People experiencing homelessness (PEH) have complex health and social care needs and most die in their early 40 s. PEH frequently use community pharmacies; however, evaluation of the delivery of structured, integrated, holistic health and social care intervention has not been previously undertaken in community pharmacies for PEH. PHOENIx (Pharmacy Homeless Outreach Engagement Non-medical Independent prescribing Rx) has been delivered and tested in Glasgow, Scotland, by NHS pharmacist independent prescribers and third sector homelessness support workers offering health and social care intervention in low threshold homeless drop-in venues, emergency accommodation and emergency departments, to PEH. Building on this work, this study aims to test recruitment, retention, intervention adherence and fidelity of community pharmacy-based PHOENIx intervention. Methods Randomised, multi-centre, open, parallel-group external pilot trial. A total of 100 PEH aged 18 years and over will be recruited from community pharmacies in Glasgow and Birmingham. PHOENIx intervention includes structured assessment in the community pharmacy of health, housing, benefits and activities, in addition to usual care, through weekly visits lasting up to six months. A primary outcome is whether to proceed to a definitive trial based on pre-specified progression criteria. Secondary outcomes include drug/alcohol treatment uptake and treatment retention; overdose rates; mortality and time to death; prison/criminal justice encounters; healthcare utilisation; housing tenure; patient-reported measures and intervention acceptability. Analysis will include descriptive statistics of recruitment and retention rates. Process evaluation will be conducted using Normalisation Process Theory. Health, social care and personal resource use data will be identified, measured and valued. Discussion If the findings of this pilot study suggest progression to a definitive trial, and if the definitive trial offers positive outcomes, it is intended that PHOENIx will be a publicly funded free-to-access service in community pharmacy for PEH. The study results will be shared with wider stakeholders and patients in addition to dissemination through medical journals and scientific conferences. Trial registration International Clinical Trial Registration ISRCTN88146807. Approved protocol version 2.0 dated July 19, 2022.

Abstract This systematic review synthesised measurement and prevalence of frailty in COPD and associations between frailty and adverse health outcomes. We searched Medline, Embase and Web of Science (1 January 2001–8 September 2021) for observational studies in adults with COPD assessing frailty prevalence, trajectories, or association with health-related outcomes. We performed narrative synthesis and random-effects meta-analyses. We found 53 eligible studies using 11 different frailty measures. Most common were frailty phenotype (n = 32), frailty index (n = 5) and Kihon checklist (n = 4). Prevalence estimates varied by frailty definitions, setting, and age (2.6–80.9%). Frailty was associated with mortality (5/7 studies), COPD exacerbation (7/11), hospitalisation (3/4), airflow obstruction (11/14), dyspnoea (15/16), COPD severity (10/12), poorer quality of life (3/4) and disability (1/1). In conclusion, frailty is a common among people with COPD and associated with increased risk of adverse outcomes. Proactive identification of frailty may aid risk stratification and identify candidates for targeted intervention.

BackgroundRight ventricular (RV) failure is the prime cause of death in patients with pulmonary arterial hypertension. Novel treatment strategies that protect the RV are needed. Empagliflozin, a sodium-glucose co-transporter-2 inhibitor, shows cardioprotective effects on the left ventricle in clinical and preclinical studies, but its direct effects on RV remain elusive. We investigated the effects of empagliflozin on RV dysfunction induced by pulmonary trunk banding (PTB).MethodsMale Wistar rats (116 ± 10 g) were randomized to PTB or sham surgery. One week after surgery, PTB animals received empagliflozin mixed into the chow (300 mg empagliflozin/kg chow; PTB-empa, n = 10) or standard chow (PTB-control, n = 10). Sham rats (Sham, n = 6) received standard chow. After five weeks, RV function was evaluated by echocardiography, cardiac MRI, and invasive pressure-volume measurements.ResultsPTB caused RV failure evident by decreased cardiac output compared with sham. PTB-empa rats had a 49% increase in water intake compared with PTB-control yet no differences in hematocrit or blood glucose. Treatment with empagliflozin decreased RV end-systolic pressures without any changes in RV cardiac output or ventricular-arterial coupling (Ees/Ea). The decrease in RV end-systolic pressure was complemented by a slight reduction in RV cross sectional area as a sign of reduced hypertrophy. Load-independent measures of RV systolic and diastolic function were not affected in PTB-empa rats compared with PTB-control.ConclusionEmpagliflozin treatment reduced RV end-systolic pressure in RV failure induced by pressure overload. Further studies are needed to elucidate whether this simply relates to a diuretic effect and/or additional independent beneficial RV effects.

Background: There has been conflicting evidence on the association between multimorbidity and blood pressure (BP) control. This study aimed to investigate this associations in people with hypertension attending primary care in Canada, and to assess whether individual long-term conditions are associated with BP control. Methods: This was a cross-sectional study in people with hypertension attending primary care in Toronto between January 1, 2017 and December 31, 2019. Uncontrolled BP was defined as systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg. A list of 11 a priori selected chronic conditions was used to define multimorbidity. Multimorbidity was defined as having ≥1 long-term condition in addition to hypertension. Logistic regression models were used to estimate the association between multimorbidity (or individual long-term conditions) with uncontrolled BP. Results: A total of 67 385 patients with hypertension were included. They had a mean age of 70, 53.1% were female, 80.6% had multimorbidity, and 35.7% had uncontrolled BP. Patients with multimorbidity had lower odds of uncontrolled BP than those without multimorbidity (adjusted OR = 0.72, 95% CI 0.68-0.76). Among the long-term conditions, diabetes (aOR = 0.73, 95%CI 0.70-0.77), heart failure (aOR = 0.81, 95%CI 0.73-0.91), ischemic heart disease (aOR = 0.74, 95%CI 0.69-0.79), schizophrenia (aOR = 0.79, 95%CI 0.65-0.97), depression/anxiety (aOR = 0.91, 95%CI 0.86-0.95), dementia (aOR = 0.87, 95%CI 0.80-0.95), and osteoarthritis (aOR = 0.89, 95%CI 0.85-0.93) were associated with a lower likelihood of uncontrolled BP. Conclusion: We found that multimorbidity was associated with better BP control. Several conditions were associated with better control, including diabetes, heart failure, ischemic heart disease, schizophrenia, depression/anxiety, dementia, and osteoarthritis.

Background Combinations of lifestyle factors (LFs) and socioeconomic status (SES) are independently associated with cardiovascular disease (CVD), cancer, and mortality. Less advantaged SES groups may be disproportionately vulnerable to unhealthy LFs but interactions between LFs and SES remain poorly understood. This review aimed to synthesise the available evidence for whether and how SES modifies associations between combinations of LFs and adverse health outcomes. Methods Systematic review of studies that examine associations between combinations of >3 LFs (eg.smoking/physical activity/diet) and health outcomes and report data on SES (eg.income/education/poverty-index) influences on associations. Databases (PubMed/EMBASE/CINAHL), references, forward citations, and grey-literature were searched from inception to December 2021. Eligibility criteria were analyses of prospective adult cohorts that examined all-cause mortality or CVD/cancer mortality/incidence. Results Six studies (n=42,467–399,537; 46.5–56.8 years old; 54.6–59.3% women) of five cohorts were included. All examined all-cause mortality; three assessed CVD/cancer outcomes. Four studies observed multiplicative interactions between LFs and SES, but in opposing directions. Two studies tested for additive interactions; interactions were observed in one cohort (UK Biobank) and not in another (National Health and Nutrition Examination Survey (NHANES)). All-cause mortality HRs (95% confidence intervals) for unhealthy LFs (versus healthy LFs) from the most advantaged SES groups ranged from 0.68 (0.32–1.45) to 4.17 (2.27–7.69). Equivalent estimates from the least advantaged ranged from 1.30 (1.13–1.50) to 4.00 (2.22–7.14). In 19 analyses (including sensitivity analyses) of joint associations between LFs, SES, and all-cause mortality, highest all-cause mortality was observed in the unhealthiest LF-least advantaged suggesting an additive effect. Conclusions Limited and heterogenous literature suggests that the influence of SES on associations between combinations of unhealthy LFs and adverse health could be additive but remains unclear. Additional prospective analyses would help clarify whether SES modifies associations between combinations of unhealthy LFs and health outcomes. Registration Protocol is registered with PROSPERO (CRD42020172588;25 June 2020).

Background People with type 2 diabetes (T2D) are at increased risk of poor outcomes from COVID-19. Vaccination can improve outcomes, but vaccine hesitancy remains a major challenge. We examined factors influencing COVID-19 vaccine uptake among people with T2D in two sub-Saharan Africa countries that adopted different national approaches to combat COVID-19, Kenya and Tanzania.Methods A mixed-methods study was conducted in February-March 2022, involving a survey of 1000 adults with T2D (500 Kenya; 500 Tanzania) and 51 in-depth interviews (21 Kenya; 30 Tanzania). Determinants of COVID-19 vaccine uptake were identified using a multivariate logistic regression model, while thematic content analysis explored barriers and facilitators.Results COVID-19 vaccine uptake was lower in Tanzania (26%) than in Kenya (75%), which may reflect an initial political hesitancy about vaccines in Tanzania. People with college/university education were four times more likely to be vaccinated than those with no education (Kenya AOR=4.25 (95% CI 1.00 to 18.03), Tanzania AOR=4.07 (1.03 to 16.12)); and people with health insurance were almost twice as likely to be vaccinated than those without health insurance (Kenya AOR=1.70 (1.07 to 2.70), Tanzania AOR=1.81 (1.04 to 3.13)). Vaccine uptake was higher in older people in Kenya, and among those with more comorbidities and higher socioeconomic status in Tanzania. Interviewees reported that wanting protection from severe illness promoted vaccine uptake, while conflicting information, misinformation and fear of side-effects limited uptake.Conclusion COVID-19 vaccine uptake among people with T2D was suboptimal, particularly in Tanzania, where initial political hesitancy had a negative impact. Policy-makers must develop strategies to reduce fear and misconceptions, especially among those who are less educated, uninsured and younger.

Abstract Titin‐dependent stiffening of cardiomyocytes is a significant contributor to left ventricular (LV) diastolic dysfunction in heart failure with preserved LV ejection fraction (HFpEF). Small heat shock proteins (HSPs), such as HSPB5 and HSPB1, protect titin and administration of HSPB5 in vitro lowers cardiomyocyte stiffness in pressure‐overload hypertrophy. In humans, oral treatment with geranylgeranylacetone (GGA) increases myocardial HSP expression, but the functional implications are unknown. Our objective was to investigate whether oral GGA treatment lowers cardiomyocyte stiffness and attenuates LV diastolic dysfunction in a rat model of the cardiometabolic syndrome. Twenty‐one‐week‐old male lean (n = 10) and obese (n = 20) ZSF1 rats were studied, and obese rats were randomized to receive GGA (200 mg/kg/day) or vehicle by oral gavage for 4 weeks. Echocardiography and cardiac catheterization were performed before sacrifice at 25 weeks of age. Titin‐based stiffness (Fpassive) was determined by force measurements in relaxing solution with 100 nM [Ca2+] in permeabilized cardiomyocytes at sarcomere lengths (SL) ranging from 1.8 to 2.4 μm. In obese ZSF1 rats, GGA reduced isovolumic relaxation time of the LV without affecting blood pressure, EF or LV weight. In cardiomyocytes, GGA increased myofilament‐bound HSPB5 and HSPB1 expression. Vehicle‐treated obese rats exhibited higher cardiomyocyte stiffness at all SLs compared to lean rats, while GGA reduced stiffness at SL 2.0 μm. In obese ZSF1 rats, oral GGA treatment improves cardiomyocyte stiffness by increasing myofilament‐bound HSPB1 and HSPB5. GGA could represent a potential novel therapy for the early stage of diastolic dysfunction in the cardiometabolic syndrome.

Background Treatment burden is the workload of healthcare for people with long-term conditions and the impact on wellbeing. A validated measure of treatment burden after stroke is needed. We aim to adapt a patient-reported measure (PRM) of treatment burden in multimorbidity, PETS (Patient Experience with Treatment and Self-Management version 2.0), to create a stroke-specific measure, PETS-stroke. We aim to examine content validity, construct validity, reliability and feasibility in a stroke survivor population. Methods 1) Adaptation of 60-item PETS to PETS-stroke using a taxonomy of treatment burden. 2) Content validity testing through cognitive interviews that will explore the importance, relevance and clarity of each item. 3) Evaluation of scale psychometric properties through analysis of data from stroke survivors recruited via postal survey (n=340). Factor structure will be tested with confirmatory factor analysis and Cronbach’s alpha will be used to index internal consistency. Construct validity will be tested against: The Stroke Southampton Self-Management Questionnaire; The Satisfaction with Stroke Care Measure; and The Shortened Stroke Impact Scale. We will explore known-groups validity by exploring the association between treatment burden, socioeconomic deprivation and multimorbidity. Test-retest reliability will be examined via re-administration after 2 weeks. Acceptability and feasibility of use will be explored via missing data rates and telephone interviews with 30 participants. Conclusions We aim to create a validated PRM of treatment burden after stroke. PETS-stroke is designed for use as an outcome measure in clinical trials of stroke treatments and complex interventions to ascertain if treatments are workable for patients in the context of their everyday lives.

Infants born pre-term are at an increased risk for developmental, behavioral, and motor delay and subsequent disability. When these problems are detected early, clinical intervention can be effective at improving functional outcomes. Current methods of early clinical assessment are resource intensive, require extensive training, and do not always capture infants’ behavior in natural play environments. We developed the Play and Neuro Development Assessment (PANDA) Gym, an affordable, mechatronic, sensor-based play environment that can be used outside clinical settings to capture infant visual and motor behavior. Using a set of classification codes developed from the literature, we analyzed videos from 24 pre-term and full-term infants as they played with each of three robotic toys designed to elicit different types of interactions—a lion, an orangutan, and an elephant. We manually coded for frequency and duration of toy interactions such as kicking, grasping, touching, and gazing. Pre-term infants gazed at the toys with similar frequency as full-term infants, but infants born full-term physically engaged more frequently and for longer durations with the robotic toys than infants born pre-term. While we showed we could detect differences between full-term and pre-term infants, further work is needed to determine whether differences seen were primarily due to age, developmental delays, or a combination.

Background People with comorbidities are under-represented in randomised controlled trials, and it is unknown whether patterns of comorbidity are similar in trials and the community. Methods Individual-level participant data were obtained for 83 clinical trials (54,688 participants) for 16 index conditions from two trial repositories: Yale University Open Data Access (YODA) and the Centre for Global Clinical Research Data (Vivli). Community data (860,177 individuals) were extracted from the Secure Anonymised Information Linkage (SAIL) databank for the same index conditions. Comorbidities were defined using concomitant medications. For each index condition, we estimated correlations between comorbidities separately in trials and community data. For the six commonest comorbidities we estimated all pairwise correlations using Bayesian multivariate probit models, conditioning on age and sex. Correlation estimates from trials with the same index condition were combined into a single estimate. We then compared the trial and community estimates for each index condition. Results Despite a higher prevalence of comorbidities in the community than in trials, the correlations between comorbidities were mostly similar in both settings. On comparing correlations between the community and trials, 21% of correlations were stronger in the community, 10% were stronger in the trials and 68% were similar in both. In the community, 5% of correlations were negative, 21% were null, 56% were weakly positive and 18% were strongly positive. Equivalent results for the trials were 11%, 33%, 45% and 10% respectively. Conclusions Comorbidity correlations are generally similar in both the trials and community, providing some evidence for the reporting of comorbidity-specific findings from clinical trials.

Abstract Background Multimorbidity (the presence of two or more chronic conditions) is common amongst people with chronic kidney disease, but it is unclear which conditions cluster together and if this changes as kidney function declines. We explored which clusters of conditions are associated with different estimated glomerular filtration rates (eGFRs) and studied associations between these clusters and adverse outcomes. Methods Two population-based cohort studies were used: the Stockholm Creatinine Measurements project (SCREAM, Sweden, 2006–2018) and the Secure Anonymised Information Linkage Databank (SAIL, Wales, 2006–2021). We studied participants in SCREAM (404,681 adults) and SAIL (533,362) whose eGFR declined lower than thresholds (90, 75, 60, 45, 30 and 15 mL/min/1.73m2). Clusters based on 27 chronic conditions were identified. We described the most common chronic condition(s) in each cluster and studied their association with adverse outcomes using Cox proportional hazards models (all-cause mortality (ACM) and major adverse cardiovascular events (MACE)). Results Chronic conditions became more common and clustered differently across lower eGFR categories. At eGFR 90, 75, and 60 mL/min/1.73m2, most participants were in large clusters with no prominent conditions. At eGFR 15 and 30 mL/min/1.73m2, clusters involving cardiovascular conditions were larger and were at the highest risk of adverse outcomes. At eGFR 30 mL/min/1.73m2, in the heart failure, peripheral vascular disease and diabetes cluster in SCREAM, ACM hazard ratio (HR) is 2.66 (95% confidence interval (CI) 2.31–3.07) and MACE HR is 4.18 (CI 3.65–4.78); in the heart failure and atrial fibrillation cluster in SAIL, ACM HR is 2.23 (CI 2.04 to 2.44) and MACE HR is 3.43 (CI 3.22–3.64). Chronic pain and depression were common and associated with adverse outcomes when combined with physical conditions. At eGFR 30 mL/min/1.73m2, in the chronic pain, heart failure and myocardial infarction cluster in SCREAM, ACM HR is 2.00 (CI 1.62–2.46) and MACE HR is 4.09 (CI 3.39–4.93); in the depression, chronic pain and stroke cluster in SAIL, ACM HR is 1.38 (CI 1.18–1.61) and MACE HR is 1.58 (CI 1.42–1.76). Conclusions Patterns of multimorbidity and corresponding risk of adverse outcomes varied with declining eGFR. While diabetes and cardiovascular disease are known high-risk conditions, chronic pain and depression emerged as important conditions and associated with adverse outcomes when combined with physical conditions.

Abstract Background Low back pain (LBP) is one of the most common reasons for disability globally. Digital interventions are a promising means of supporting people to self-manage LBP, but implementation of digital interventions has been suboptimal. An artificial intelligence-driven app, selfBACK, was developed to support self-management of LBP as an adjunct to usual care. To better understand the process of implementation from a participant perspective, we qualitatively explored factors influencing embedding, integrating, and sustaining engagement with the selfBACK app, and the self-perceived effects, acceptability, and satisfaction with the selfBACK app. Methods Using a qualitative interview study and an analytic framework approach underpinned by Normalization Process Theory (NPT), we investigated the experiences of patients who participated in the selfBACK randomized controlled trial (RCT). Interviews focused on the motivation to participate in the RCT, experiences of using the selfBACK app, and views about future intended use and potential of using digital health interventions for self-management of LBP. Participants were purposively sampled to represent diversity in age, sex, and implementation reflected by a proxy measure of number of app-generated self-management plans during the first three months of RCT participation. Results Twenty-six participants aged 21–78, eleven females and fifteen men, with two to fourteen self-management plans, were interviewed between August 2019 and April 2020. A broad range of factors influencing implementation of selfBACK within all constructs of NPT were identified. Key facilitating factors were preferences and beliefs favoring self-management, a friendly, motivational, and reassuring supporter, tailoring and personalization, convenience and ease of use, trustworthiness, perceiving benefits, and tracking achievements. Key impeding factors were preferences and beliefs not favoring self-management, functionality issues, suboptimal tailoring and personalization, insufficient time or conflicting life circumstances, not perceiving benefits, and insufficient involvement of health care practitioners. Self-perceived effects on pain and health, behavior/attitude, and gaining useful knowledge varied by participant. Conclusions The high prevalence of LBP globally coupled with the advantages of providing help through an app offers opportunities to help countless people. A range of factors should be considered to facilitate implementation of self-management of LBP or similar pain conditions using digital health tools.

Abstract Background The applicability of randomised controlled trials of pharmacological agents to older people with frailty/multimorbidity is often uncertain, due to concerns that trials are not representative. However, assessing trial representativeness is challenging and complex. We explore an approach assessing trial representativeness by comparing rates of trial serious adverse events (SAE) to rates of hospitalisation/death in routine care. Methods This was an observational analysis of individual (125 trials, n=122,069) and aggregate-level drug trial data (483 trials, n=636,267) for 21 index conditions compared to population-based routine healthcare data (routine care). Trials were identified from ClinicalTrials.gov . Routine care comparison from linked primary care and hospital data from Wales, UK (n=2.3M). Our outcome of interest was SAEs (routinely reported in trials). In routine care, SAEs were based on hospitalisations and deaths (which are SAEs by definition). We compared trial SAEs in trials to expected SAEs based on age/sex standardised routine care populations with the same index condition. Using IPD, we assessed the relationship between multimorbidity count and SAEs in both trials and routine care and assessed the impact on the observed/expected SAE ratio additionally accounting for multimorbidity. Results For 12/21 index conditions, the pooled observed/expected SAE ratio was

Background Most people living with multiple long-term condition multimorbidity (MLTC-M) are under 65 (defined as ‘early onset’). Earlier and greater accrual of long-term conditions (LTCs) may be influenced by the timing and nature of exposure to key risk factors, wider determinants or other LTCs at different life stages. We have established a research collaboration titled ‘MELD-B’ to understand how wider determinants, sentinel conditions (the first LTC in the lifecourse) and LTC accrual sequence affect risk of early-onset, burdensome MLTC-M, and to inform prevention interventions. Aim Our aim is to identify critical periods in the lifecourse for prevention of early-onset, burdensome MLTC-M, identified through the analysis of birth cohorts and electronic health records, including artificial intelligence (AI)-enhanced analyses. Design We will develop deeper understanding of ‘burdensomeness’ and ‘complexity’ through a qualitative evidence synthesis and a consensus study. Using safe data environments for analyses across large, representative routine healthcare datasets and birth cohorts, we will apply AI methods to identify early-onset, burdensome MLTC-M clusters and sentinel conditions, develop semi-supervised learning to match individuals across datasets, identify determinants of burdensome clusters, and model trajectories of LTC and burden accrual. We will characterise early-life (under 18 years) risk factors for early-onset, burdensome MLTC-M and sentinel conditions. Finally, using AI and causal inference modelling, we will model potential ‘preventable moments’, defined as time periods in the life course where there is an opportunity for intervention on risk factors and early determinants to prevent the development of MLTC-M. Patient and public involvement is integrated throughout.

The detrimental effects of loneliness and social isolation on health and well-being outcomes are well documented. In response, governments, corporations, and community-based organizations have begun leveraging tools to create interventions and policies aimed at reducing loneliness and social isolation at scale. However, these efforts are frequently hampered by a key knowledge gap: when attempting to improve specific health and well-being outcomes, decision-makers are often unsure whether to target loneliness, social isolation, or both. Filling this knowledge gap will inform the development and refinement of effective interventions. Using data from the Health and Retirement Study (13,752 participants (59% women and 41% men, mean [SD] age = 67 [10] years)), we examined how changes in loneliness and social isolation over a 4-year follow-up period (from t0:2008/2010 to t1:2012/2014) were associated with 32 indicators of physical-, behavioral-, and psychosocial-health outcomes 4-years later (t2:2016/2018). We used multiple logistic-, linear-, and generalized-linear regression models, and adjusted for sociodemographic, personality traits, pre-baseline levels of both exposures (loneliness and social isolation), and all outcomes (t0:2008/2010). We incorporated data from all participants into the overall estimate, regardless of whether their levels of loneliness and social isolation changed from the pre-baseline to baseline waves. After adjusting for a wide range of covariates, we observed that both loneliness and social isolation were associated with several physical health outcomes and health behaviors. However, social isolation was more predictive of mortality risk and loneliness was a stronger predictor of psychological outcomes. Loneliness and social isolation have independent effects on various health and well-being outcomes and thus constitute distinct targets for interventions aimed at improving population health and well-being.

Objective Social, biological and environmental factors in early-life, defined as the period from preconception until age 18, play a role in shaping the risk of multiple long-term condition multimorbidity. However, there is a need to conceptualise these early-life factors, how they relate to each other, and provide conceptual framing for future research on aetiology and modelling prevention scenarios of multimorbidity. We develop a conceptual framework to characterise the population-level domains of early-life determinants of future multimorbidity. Method This work was conducted as part of the Multidisciplinary Ecosystem to study Lifecourse Determinants and Prevention of Early-onset Burdensome Multimorbidity (MELD-B) study. The conceptualisation of multimorbidity lifecourse determinant domains was shaped by a review of existing research evidence and policy, and co-produced with public involvement via two workshops. Results Early-life risk factors incorporate personal, social, economic, behavioural and environmental factors, and the key domains discussed in research evidence, policy, and with public contributors included adverse childhood experiences, socioeconomics, the social and physical environment, and education. Policy recommendations more often focused on individual-level factors as opposed to the wider determinants of health discussed within the research evidence. Some domains highlighted through our co-production process with public contributors, such as religion and spirituality, health screening and check-ups, and diet, were not adequately considered within the research evidence or policy. Conclusions This co-produced conceptualisation can inform research directions using primary and secondary data to investigate the early-life characteristics of population groups at risk of future multimorbidity, as well as policy directions to target public health prevention scenarios of early-onset multimorbidity.

Introduction Community-acquired pneumonia has high mortality and is associated with significant healthcare costs. In older adults with community-acquired pneumonia neutrophil dysfunction has been identified and is associated with poor outcomes for patients. Immunometabolism is a rapidly developing field which links immune cell function to metabolism. This study aims to explore neutrophil metabolism in community-acquired pneumonia.Methods and analysis Pneumonia Metabolism in Ageing study is a prospective observational study recruiting older adults hospitalised with community-acquired pneumonia to examine neutrophil function and metabolic status. Controls will be older adults with no acute illness. The primary endpoint is neutrophil chemotaxis.Ethics and dissemination The study has ethical approval from the Research Ethics Committee Wales, reference 19/WA/0299. This study involves participants who may lack the capacity to consent to research involvement, in this situation, personal or professional assent will be sought. The results from this study will be submitted for publication in peer-reviewed journals and disseminated at local and international conferences.

Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is unknown. Using RNA-seq we show that acidosis produces system level transcriptional change in M.tb infected human macrophages regulating almost 4000 genes. Acidosis specifically upregulated extracellular matrix (ECM) degradation pathways with increased expression of Matrix metalloproteinases (MMPs) which mediate lung destruction in Tuberculosis. Macrophage MMP-1 and -3 secretion was increased by acidosis in a cellular model. Acidosis markedly suppresses several cytokines central to control of M.tb infection including TNF-α and IFN-γ. Murine studies demonstrated expression of known acidosis signaling G-protein coupled receptors OGR-1 and TDAG-8 in Tuberculosis which are shown to mediate the immune effects of decreased pH. Receptors were then demonstrated to be expressed in patients with TB lymphadenitis. Collectively, our findings show that an acidic microenvironment modulates immune function to reduce protective inflammatory responses and increase extracellular matrix degradation in Tuberculosis. Acidosis receptors are therefore potential targets for host directed therapy in patients.

Abstract Persistent abnormalities in microcirculatory function are associated with poor clinical outcomes in patients with circulatory shock. We sought to identify patients with acutely reversible microcirculatory dysfunction using a low-dose topical nitroglycerin solution and handheld videomicroscopy during circulatory shock after cardiac surgery. Forty subjects were enrolled for the study, including 20 preoperative control and 20 post-operative patients with shock. To test whether microcirculatory dysfunction is acutely reversible during shock, the sublingual microcirculation was imaged with incident dark field microscopy before and after the application of 0.1 mL of a 1% nitroglycerin solution (1 mg/mL). Compared to the control group, patients with shock had a higher microcirculation heterogeneity index (MHI 0.33 vs. 0.12, p 1.8 SD from shock baseline. Hemodynamics and vasoactive doses did not change during the 30-min study period. Our findings suggest a topical nitroglycerin challenge with handheld videomicroscopy can safely assess for localized recruitment of the microcirculatory blood flow in patients with circulatory shock and may be a useful test to identify nitroglycerin responsiveness.